Genetic deletion of Regulators of G protein Signaling (RGS) protein activity enhances buprenorphine antinociception while limiting withdrawal behaviors associated with chronic administration

Abstract

Understanding the mechanisms that govern opioid signaling is important to improve therapy for pain while limiting abuse potential. Opioid signaling is controlled by regulators of G protein signaling (RGS) proteins. In vitro evidence suggests that partial efficacy mu‐opioid agonists such as buprenorphine are more sensitive to RGS protein regulation than those that are fully efficacious. To determine the relevance of this in vivo, transgenic “knock‐in” mice were developed that express RGS‐insensitive Gαi2 (G184S; RGS‐i). Buprenorphine was twice as efficacious in RGS‐i animals compared to wild‐type littermates in antinociceptive tests. However, morphine activity was identical in animals of either genotype. In contrast, when administered chronically (5‐day treatment), both buprenorphine and morphine induced the same degree of tolerance in RGS‐i and wild‐type animals, indicating that mechanisms underlying opioid tolerance are insensitive to RGS regulation of Gαi2. Importantly, withdrawal behaviors, such as naltrexone‐precipitated jumping, were substantially reduced in chronically‐treated RGS‐i mice relative to wild‐type littermates. These data suggest that inhibition of RGS protein activity at Gαi2 leads to enhanced antinociception but reduced physical dependence to buprenorphine. Supported by DA04087, GM39561, T32 DA007268, and the Bower, Bennet, & Bennet Endowed Chair Research Award.